Pinheiro Marina, Amenitsch Heinz, Reis Salette
LAQV, REQUIMTE, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, 4050-313 Porto, Portugal.
Institute of Inorganic Chemistry, Graz University of Technology, Stremayergasse 6/V, 8010 Graz, Austria.
Membranes (Basel). 2019 Oct 30;9(11):141. doi: 10.3390/membranes9110141.
This work focuses on the interaction of the novel and representative antituberculosis (anti-TB) drug bedaquiline (BDQ) with different membrane models of eukaryotic and prokaryotic cells. The effect of BDQ on eukaryotic cell membrane models was assessed using liposomes, namely, multilamellar vesicles (MLVs) made of 1,2-dimyristoyl--glycero-3-phosphocholine (DMPC) and also a mixture of DMPC and cholesterol (CHOL) (8:2 molar ratio). To mimic the prokaryotic cell membrane, 1,2-dimyristoyl--glycero-3-phospho--(1-glycerol) (DMPG) and 1,1'2,2'-tetra-oleoyl-cardiolipin (TOCL) were chosen. Powerful biophysical techniques were employed, including small-angle X-ray scattering (SAXS) and wide-angle X-ray scattering (WAXS), to understand the effect of BDQ on the nanostructure of the membrane models. The results showed that BDQ demonstrated a pronounced disordering effect in the bacterial cell membrane models, especially in the membrane model with cardiolipin (CL), while the human cell membrane model with large fractions of neutral phospholipids remained less affected. The membrane models and techniques provide detailed information about different aspects of the drug-membrane interaction, thus offering valuable information to better understand the effect of BDQ on their target membrane-associated enzyme as well as its side effects on the cardiovascular system.
这项工作聚焦于新型代表性抗结核药物贝达喹啉（BDQ）与真核细胞和原核细胞不同膜模型的相互作用。使用脂质体评估BDQ对真核细胞膜模型的影响，脂质体即由1,2 - 二肉豆蔻酰 - sn - 甘油 - 3 - 磷酸胆碱（DMPC）制成的多层囊泡（MLV），以及DMPC与胆固醇（CHOL）的混合物（摩尔比8:2）。为模拟原核细胞膜，选用了1,2 - 二肉豆蔻酰 - sn - 甘油 - 3 - 磷酸 - （1 - 甘油）（DMPG）和1,1',2,2'-四油酰 - 心磷脂（TOCL）。采用了强大的生物物理技术，包括小角X射线散射（SAXS）和广角X射线散射（WAXS），以了解BDQ对膜模型纳米结构的影响。结果表明，BDQ在细菌细胞膜模型中表现出明显的无序化作用，尤其是在含有心磷脂（CL）的膜模型中，而含有大量中性磷脂的人类细胞膜模型受影响较小。这些膜模型和技术提供了有关药物 - 膜相互作用不同方面的详细信息，从而为更好地理解BDQ对其靶膜相关酶的作用以及对心血管系统的副作用提供了有价值的信息。
